Transition-Metal-Free Cross-Dehydrogenative Coupling of Triazines with 5,7-Dihydroxycoumarins

Abstract

A new method for the direct metal-free C–H functionalization of electron-deficient triazines with fragments of naturally occurring and synthetic 5,7-dihydroxycoumarins is reported. It has been found that the reaction of 5,7-dihydroxycoumarins with triazines proceeds under mild conditions, showing a high chemo- and regioselectivity.

Key words

C–H arylation - dehydrogenative coupling - triazines - halogen-free metal-free reaction

• References and Notes

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• 15 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazines 6a and 6b (Procedure A) To a MeOH solution (15 mL) or suspension of 5 (1 mmol) and 6a or 6b (1 mmol), BF₃·OEt₂ (1 mL) was carefully added. The mixture was heated under reflux with stirring for 4 h, while ­dissolution of the starting materials, followed by precipitation of product (for 7a–e), was observed. In the case of products 8a–e the reaction mixture was poured into sat. aq NaHCO₃ (50 mL). The precipitate was filtered off, refluxed with acetone, and dried at 100 °C. 5-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-8-yl)-6-phenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (7a) Yield 310 mg, 85%; white powder, mp 290–292 °C (dec.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.48 (d, ⁴ J = 1 Hz, 3 H, CH₃), 5.87 (d, ⁴ J = 1 Hz, 1 H, C3′H), 6.20 (s, 1 H, C5H), 6.29 (s, 1 H, C6′H), 6.94 (br s, 1 H, N4H), 7.22–7.25 (m, 3 H, H_Ph), 7.55–7.57 (m, 2 H, H_Ph), 10.05 (s, 1 H, N2H), 10.56 (br s, 1 H, OH), 10.76 (br s, 1 H, OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.6 (CH₃), 45.8 (C5), 95.4 (C6′), 101.9 (C4a′), 106.6 (C8′), 108.6 (C3′), 125.0 (C_o), 128.1 (C _m ), 128.4 (C _p ), 135.3 (C _i ), 139.0 (C6), 149.7 (C3), 155.2 (C4′), 157.3 (C5′), 158.0 (C8a′), 159.3 (C7′), 160.0 (C2′) ppm. IR: 1696, 1664, 1550, 1356 cm^–1. Anal. Calcd for C₁₉H₁₅N₃O₅: C, 62.46; H, 4.14; N, 11.50. Found: C, 62.40; H, 3.99; 11.67. 5,7-Dihydroxy-4-methyl-8-(3-(methylthio)-2,5-dihydro-1,2,4-triazin-5-yl)-chromen-2(2H)-one (8a) Yield 249 mg, 78%; pale beige powder, mp 235–237 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.33 (s, 3 H, SCH₃), 2.51 (s, 3 H, CH₃), 4.71 (s, 1 H, C5′H), 5.87 (s, 1 H, C3H), 6.32 (s, 1 H, C6H), 6.81 (s, 1 H, C6′H), 10.55 (br s, 1 H, NH), 11.01 (br s, 1 H, OH), 11.40 (br s, 1 H, OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.1 (SCH₃), 23.7 (CH₃), 51.8 (C5), 99.4 (C6′), 102.3 (C4a′), 102.7 (C8′), 108.7 (C3′), 140.9 (C6), 154.1 (C8a′), 155.2 (C5′), 155.3 (C3), 157.1 (C4′), 159.6 (C2′), 160.5 (C7′) ppm. IR: 1721, 1686, 1601, 1567, 1360 cm^–1. Anal. Calcd for C₁₄H₁₃N₃O₄S: C, 52.66; H, 4.10; N, 13.16. Found: C, 52.73; H, 4.28; N, 13.13.
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• 17 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazine 6c (Procedure B) To AcOH (15 mL) 5a–e (1 mmol), 6c (1 mmol), and MsOH (1 mL) were added. The mixture was allowed to stand for 24–72 h at r.t., while precipitation of product was observed. The precipitate was filtered off, washed with acetone, and dried at 100 °C yielding pure 9a–e.8-(3,6-Diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-5,7-dihydroxy-4-methyl-2H-chromen-2-one Methanesulfonate (9a) Yield 469 mg, 90%; pale yellow needles, mp 233–235 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.36 (s, 3 H, CH₃SO₃ ^–), 2.46 (s, 3 H, CH₃), 5.93 (s, 1 H, C3′H), 6.44 (s, 1 H, C6′H), 6.66 (s, 1 H, C5H), 7.38–7.48 (m, 3 H, H _p + H _o ), 7.63–7.67 (m, 2 H, H _m ), 7,75–7.85 (m, 5 H, Ph), 11.01 (s, 1 H, C5′OH), 11.08 (s, 1 H, NH), 11.44–11.54 (br s, 1 H, C7′OH), 13.44 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.7 (CH₃), 39.5 (CH₃SO₃ ^-), 42.4 (C5), 99.5 (C6′), 102.9 (C4a′), 105.0 (C8′), 109.3 (C3′), 125.1 (C _i ), 125.9 (C _m ), 128.1 (C _o ), 128.7 (C _o ), 129.3 (C _m ), 131.3 (C _p ), 132.8 (C6), 134.1 (C_p), 148.8 (C _i ), 152.7 (C3), 154.8 (C8a′), 155.6 (C4′), 158.9 (C5′), 158.9 (C2′), 159.4 (C7′) ppm. IR: 1696, 1603, 1558, 1189 cm^–1. Anal. Calcd for C₂₆H₂₃N₃O₇S: C, 59.88; H, 4.45; N, 8.06. Found: C, 59.79; H, 4.40; N, 8.14.
• 18 Azev YA, Shorshnev SV, Gabel D. Mendeleev Commun. 2001; 11: 234
• 19 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazine 10 (Procedure C) 5,7-Dihydroxycoumarin 5a–e (1 mmol) and triazine 10 (1 mmol) were dissolved in TFA (10 mL) and CHCl₃ (10 mL), and the reaction solution was heated under reflux for 4 h. Then to the reaction mixture was added 2-PrOH (15 mL), the mixture was cooled, and the precipitate was filtered off. The product 11a–e was recrystallized from 1,4-dioxane and dried at 100 °C for 4 h. 6-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-8-yl)-1,3,5-triazin-2,4-dione (11a) Yield 168 mg, 55%; pinkish powder, mp 289–291 °C (dec.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.51 (s, 3 H, CH₃), 5.90 (s, 1 H, C3′H), 6.11 (s, 1 H, C6H), 6.36 (s, 1 H, C6′H), 7.52 (s, 2 H, N1H, N5H), 9.12 (s, 1 H, N3H), 10.65 (s, 1 H, OH), 10.70 (br s, 1 H, OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.7 (CH₃), 55.4 (C6), 99.1 (C6′), 101.8 (C4a′), 106.2 (C8′), 108.7 (C3′), 152.2 (C2, C4), 154.2 (C8a′), 155.3 (C4′), 157.6 (C5′), 159.4 (C7′), 160.0 (C2′) ppm. IR: 1704, 1664, 1610, 1575, 1360 cm^–1. Anal. Calcd for C₁₃H₁₁N₃O₆: C, 51.15; H, 3.63; N, 13.77. Found: C, 51.19; H, 3.58; N, 13.69.
• 20 General Procedure for the Oxidation of Dihydroadducts To a solution of 8a–e (0.5 mmol) in AcOH (5 mL) was added an acetone solution (4 mL) of chloranil (0.5 mmol, 123 mg). The reaction mixture was heated at 40 °C for 24 h, cooled, diluted with acetone (10 mL) to complete formation of the precipitate, and the precipitate was filtered off and washed with acetone to give pure 15a–e. 5,7-Dihydroxy-4-methyl-8-(3-(methylthio)-1,2,4-triazin-5-yl)-chromen-2(2H)-one (15a) Yield 212 mg, 67%; yellow powder, mp > 300 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.53 (s, 3 H, CH₃), 2.63 (s, 3 H, SCH₃), 5.96 (C3H), 6.46 (s, 1 H, C6H), 9.34 (s, 1 H, C6′H), 11.1–11.5 (br s, 2 H, 2 OH) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.2 (SCH₃), 23.7 (CH₃), 99.1 (C6′), 101.1 (C8′), 102.6 (C4a′), 109.6 (C3′), 147.3 (C6), 153.3 (C5), 154.9 (C8a′), 155.0 (C4′), 158.9 (C2′), 160.2, 160.4 (C7′, C5′), 171.8 (C3) ppm. IR: 1740, 1483, 1404, 1285 cm^–1. Anal. Calcd for C₁₄H₁₁N₃O₄S: C, 52.99; H, 3.49; N, 13.24. Found: C, 53.05; H, 3.46; N, 13.30.